Prostaglandin E2 Suppresses Chemokine Production in Human Macrophages through the EP4 Receptor

Abstract

Pro-inflammatory pathways participate in the pathogenesis of atherosclerosis. However, the role of endogenous anti-inflammatory pathways in atheroma has received much less attention. Therefore, using cDNA microarrays, we screened for genes regulated by prostaglandin E 2 (PGE 2 ), a potential endogenous anti-inflammatory mediator, in lipopolysaccharide (LPS)-treated human macrophages (M⌽). PGE 2 (50 nM) attenuated LPS-induced mRNA and protein expression of chemokines including monocyte chemoattractant protein-1, interleukin-8, macrophage inflammatory protein-1␣ and -1␤, and interferon-inducible protein-10. PGE 2 also inhibited the tumor necrosis factor-␣-, interferon-␥-, and interleukin-1␤-mediated expression of these chemokines. In contrast to the case of M⌽, PGE 2 did not suppress chemokine expression in human endothelial and smooth muscle cells (SMC) treated with LPS and pro-inflammatory cytokines. To assess the potential paracrine effect of endogenous PGE 2 on macrophagederived chemokine production, we co-cultured M⌽ with SMC in the presence of LPS. In these co-cultures, cyclooxygenase-2-dependent PGE 2 production exceeded that in the mono-cultures, and MIP-1␤ declined significantly compared with M⌽ cultured without SMC. We further documented prominent expression of the PGE 2 receptor EP4 in M⌽ in both culture and human atheroma. Moreover, a selective EP4 antagonist completely reversed PGE 2 -mediated suppression of chemokine production. Thus, endogenous PGE 2 may modulate inflammation during atherogenesis and other inflammatory diseases by suppressing macrophage-derived chemokine production via the EP4 receptor.

Nickel Alterations of TLR2-Dependent Chemokine Profiles in Lung Fibroblasts Are Mediated by COX-2

“…Four transmembrane G proteincoupled PGE2 receptor subtypes (EP1-4) mediate the biological actions of PGE2. Depending on cell-specific expression of the different EP receptor subtypes, PGE2 can either suppress (44) or stimulate CXCL8 production (26,45). In the current study, PGE2 alone (10 27 M) did not stimulate CXCL8.…”

P2 receptor-mediated signaling in mast cell biology

“…Feng et al [59] suggested that P2Y receptors activate inhibitory pathways that suppress the transcription of cytokines. In accordance with this hypothesis, several publications have demonstrated that G s protein-coupled receptors which interfere with activation of immune cells (e.g., receptors for PGE 2 and β 2 adrenergic receptor) activate adenylate cyclase and initiate cAMP-dependent inhibitory signaling pathways [80,81]. Indeed, ATP and ADP triggered cAMP accumulation, phosphorylation of CREB, and the upregulation of CREB-dependent inducible cAMP early repressor, an inhibitor of NF-AT and AP-1-mediated cytokine transcription, presumably via P2Y 11 receptor [59].…”

Prostaglandin E receptor 4 (PTGER4) involved in host protection against immune challenge in oyster, Crassostrea hongkongensis

“…PTGER4 has been shown to function as a key regulator in host defense and the immune response in vertebrates [13,14]. However, Fig.…”

“…It was reported that the PTGER4 has several sites, including S103, T168, Y186, F191, L195, S285, and D311, which were identified as being essential of the interaction of PGE2 [12]. Activation of PTGER4 by PGE2 has been implicated in a wide variety of biological processes, including the regulation of immune responses and cytokine production [13,14].…”

“…It was shown that PGE2-PTGER4 signaling in mammalian macrophages suppressed the stimulus-induced expression of certain proinflammatory genes, including tumor necrosis factor (TNF)-a, interferon (IFN)-b and macrophage inflammatory protein (MIP)-1b [14,17]. Reportedly, in the setting of LPS stimulation, PGE2 signaling via PTGER4 decreased the levels of interleukin-1beta (IL-1b) [18] and inducible nitric oxide synthase (iNOS) [19] in microglia.…”